Lantibiotics are antimicrobial peptides containing the unique bis-amino acids lanthionine and beta-methyllanthionine. While previous syntheses of lanthionine have often involved the coupling of precursors derived from D-serine and L-cysteine, we here report an inverted strategy whereby D-cysteine and L-serine are employed as building blocks. This approach provides for a concise preparation of tetra-orthogonally protected (2R,6S)-lanthionines while allowing convenient introduction of orthogonal protecting groups not previously incorporated into lanthionines.